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Coming dissertations at MedFak

  • MYC-driven Medulloblastoma : New Targeted Therapies and Mechanisms of Recurrence Author: Anna Borgenvik Link: Publication date: 2021-09-24 10:04

    Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the posterior fossa but presents with distinct histological and molecular features. Hence, medulloblastoma is divided into four molecular subgroups, WNT, SHH, Group 3, and Group 4. The overall 5-year survival is ~70% across subgroups but varies with high- and low-risk disease. Standard treatment of medulloblastoma consists of maximal safe tumor resection, radiotherapy, and adjuvant chemotherapy. Despite the rather high success rate of treatment for many patients it also comes with severe long-term debilitating side effects. 

    MYC proteins are master regulators of gene expression often deregulated in cancer. MYC family members MYC and MYCN share similar roles and are found overexpressed or amplified in most medulloblastoma subgroups and correlate with a poor prognosis. 

    Medulloblastoma dissemination and recurrence patterns differ between subgroups but are always associated with a poor prognosis. Recurrent medulloblastoma is not yet curable and will lead to death. 

    In this thesis, we present the first transgenic mouse model of medulloblastoma recurrence and highlight the role of the transcription factor SOX9 in MYC-driven relapse mechanisms. By studying this recurrence model and matched primary-recurrent patient samples we propose a mechanism in which treatment-refractory and quiescent SOX9-positive cells in Group 3 medulloblastoma are necessary for tumor relapse, and how the recurrent tumors can be specifically treated with MGMT inhibitors and doxorubicin.

    In addition, we address efficient treatment options of primary MYC-driven medulloblastoma where BET bromodomain inhibition (JQ1) in combination with CDK2 inhibition (milciclib) of human Group 3 medulloblastoma will lead to apoptosis and prolonged survival of xenografted mice. This is explained by a dual hit on MYC transcriptional output and MYC protein stability exerted by JQ1 and milciclib respectively. Finally, in a different novel transgenic model of MYC-driven medulloblastoma, we show how temporal Cdk2 knock-out has no effect on MYC protein stability but slows down proliferation and prolongs survival of allografted mice. 

    The need for better treatments and increased understanding of recurrent medulloblastoma is huge. To that end, this thesis focuses on and addresses novel treatments, the role of the cell cycle protein CDK2 as well as relapse mechanisms depending on dormant SOX9-positive cells in highly aggressive MYC-driven medulloblastoma.

  • Adulthood Outcomes of Child and Adolescent Depression : From Mental Health to Social Functioning Author: Iman Alaie Link: Publication date: 2021-09-23 09:28

    Depression is a common mental disorder affecting people across the lifespan, with first onset frequently occurring in the teenage years. The disorder is costly to society and constitutes one of the leading causes of disability in youths and adults worldwide. Research demonstrates that depression in childhood or adolescence is linked to adverse adult consequences, including mental health problems, physical health issues, various social difficulties, and economic hardships. While the specific factors and mechanisms associated with these long-term adversities are not well understood, previous studies point to the relevance of considering the heterogeneity in early-life depression.

    The overarching aim of this doctoral thesis was to shed more light on long-term outcomes of childhood and adolescent depression across multiple life domains. This work made use of extensive follow-up data gathered in Sweden and USA, as part of two community-based longitudinal cohort studies of depressed and nondepressed youths prospectively followed into adulthood. In the Uppsala Longitudinal Adolescent Depression Study, participants were interviewed around age 16 (n=631) and age 31 (n=409). Using linkage to nationwide population-based registries, participants were followed up around age 40 (n=576). In the Great Smoky Mountains Study, participants were interviewed at repeated occasions in childhood and adolescence (n=1,420), and at further follow-ups in adulthood extending up to age 30 (n=1,336).

    Findings from this work suggest that childhood/adolescent depression can have long-lasting associations with a broad spectrum of adverse outcomes. First, the risk of adult depression is known to be elevated among those exposed to depression in early life; however, depressed youths experiencing major conflicts with parents may be at an additionally increased risk of subsequent depression recurrence. Second, early-life depression was found to be associated with higher levels of adult psychiatric disorders, and also with worse health, criminal, and social functioning, even when accounting for a multitude of potential confounders. Third, early-life depression was predictive of poor labor market outcomes, especially for those with persistent depression. This link was partially mediated by the course of depression. Fourth, the welfare burden associated with early depression amounted to considerable public expenditures in adulthood, particularly for those with persistent depression or comorbid psychiatric conditions such as anxiety and disruptive behavior disorders.

    The adverse long-term consequences in the wake of early-life depression underscore the importance of prevention and treatment approaches that are both efficacious and cost-effective. Such targeted efforts may have the potential to avert later ill-health, impairment, and possibly also economic disadvantage.

  • Adverse drug effects on glucose and lipid metabolism: is human adipose tissue of importance? Author: Assel Sarsenbayeva Link: Publication date: 2021-09-22 14:53

    Many pharmacological agents that are widely prescribed in clinical practice have adverse metabolic effects, such as hyperglycaemia, insulin resistance, and diabetes. Among such drugs are antipsychotics, prescribed for treatment of schizophrenia; statins, which inhibit cholesterol synthesis and prevent cardiovascular events; finally, potent anti-inflammatory agents, glucocorticoids. This thesis is focused on investigating the direct effects of second-generation antipsychotics (SGAs), statins, and glucocorticoids on human adipose tissue metabolism and inflammation, particularly in the light of macrophage-adipocyte cross talk.

    In Paper I, the direct effects of SGAs on adipose tissue glucose and lipid metabolism were studied. SGAs had a mild effect on adipocyte glucose uptake and lipolysis at therapeutic concentrations. At supra-therapeutic concentrations, the drugs demonstrated anti-inflammatory potential, reducing the expression of pro-inflammatory genes in the adipose tissue.

    In Paper II, the anti-inflammatory potential of SGAs and dexamethasone was further explored. The effects of the drugs on macrophage phenotype and communication with adipocytes were addressed. SGAs at supra-therapeutic concentrations exerted mild anti-inflammatory effects on macrophages, while dexamethasone acted as a potent anti-inflammatory agent and promoted alternatively activated M2 macrophage phenotype. Macrophages, in turn, induced marked upregulation of pro-inflammatory genes in adipocytes, which was partially reversed by dexamethasone, while SGAs had no effects on macrophage-adipocyte communication.

    In Paper III, we examined the association of statin therapy on systemic insulin resistance and direct effects statins on human adipose tissue and pancreatic islets functions. We also studied association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the enzyme involved in cholesterol synthesis, and genetic inhibition of HMGCR seen with certain polymorphisms with adipose tissue and plasma metabolome. Our study demonstrated minor direct effects of statins on human adipose tissue metabolism and insulin secretion in pancreatic islets. We observed that HMGCR expression was associated with a number of metabolic and mitochondrial pathways in the adipose tissue, while LDL-lowering HMGCR polymorphism was negatively associated with plasma phosphatidylcholines and sphingomyelins. 

    In Paper IV we studied the effects of glucocorticoids on adipose tissue fibrosis, particularly in terms of macrophage-preadipocyte communication. Together with inflammation, adipose tissue fibrosis impairs adipocyte metabolism and functions. We observed that glucocorticoids at high concentrations have pro-fibrotic effects in adipose tissue. Macrophage-preadipocyte co-culture data showed that macrophages stimulate phenotypic switch of preadipocytes to pro-fibrotic myofibroblasts, and this effect was exacerbated by dexamethasone. Our findings suggest that pro-fibrotic effects of excess glucocorticoids on adipose tissue are at least partially mediated via their effects on macrophage-preadipocyte communication.

    We conclude that SGAs and statins have a mild direct effect on adipose tissue metabolism and their diabetogenic effects could to be induced via other organs, such as brain, liver or muscle. By contrast, glucocorticoids, directly impair adipose tissue metabolism and exacerbates adipose tissue fibrosis, which could be one of the contributing factors to their metabolic adverse effects.